Summary Alzheimer?s disease (AD) and AD related dementias (ADRD) are unpreventable, incurable and remain poorly understood.Theirhallmarkpathologyconsistsofmisfoldedproteinsincharacteristic?inclusions?withinsubsets ofneuronsandglialcellsofthebrain.Misfoldingofthemembrane-associatedprotein?-synuclein(?S)iscentral toADRD.Inclusionsrichin?Sincorticalanddopaminergic(DA)neuronsarethehallmarklesionsofdementia withLewybodies(DLB)andParkinsondiseasewithdementia(PDD).But?Sinclusionsarealsofoundin>50% of AD cases, correlating with cognitive decline and frequently colocalizing with tau pathology. ?S pathology is strikingly heterogeneous and poorly understood. Common ?S pathology comprises vesicle-rich ?pale bodies? (PBs), amyloid-rich Lewy bodies (LBs), or combinations of these. PBs have indeed been discussed as precursors of LBs, but what gives rise to PBs and how they may convert into LBs remains enigmatic. The ultrastructural features of PBs and LBs parallel enormous interest in the field in both amyloid and vesicle- traffickingpathologiesinPD.Inexperimentalsettings,theseedingofneuronswithpre-formedfibrilsleadstoLB- like amyloidaggregates. These aggregates can under certain conditions spreadand self-template inadjacent cells.Differentamyloidfiberconformers(?strains?)leadtodifferentpatternsofneurodegeneration,withdiffering levels of phosphorylated ?S and tau. Human genetic studies have repeatedly implicated perturbed vesicle traffickingand(membrane)lipidhomeostasisasafundamentalandunifyingfeatureindisparateformsofADRD. We hypothesize that altered cellular, and especially lipid, microenvironments cantrigger ?S amyloid formation andthedevelopmentofdifferentstrainsandpathologies.Anincreasingbodyofevidence,includingworkfrom our groups, indeed suggests that ?S toxicity and aggregation can be modulated by altering cellular fatty acid (FA)saturationorsphingolipid(SL)compositionthroughmanipulationofglucocerebrosidase(GBA)andstearoyl- coA desaturase (SCD), respectively. We propose to dissect the influence of these pathways on PB and LB formation and transition in the most disease-relevant patient-derived induced pluripotent stem cell (iPSC) models. Importantly, we will employ patient brain-derived ?seed? as the most relevant trigger for neuronal ?S aggregation.Theuseofbothpatient-specificcelltypesandmisfoldedproteinconformerswillallowustocapture ?in the dish? bothsides of the toxic equation in neurodegeneration. We recognize the importance, but also the limitations, of postmortem end-stage pathology in delineating disease mechanisms, and propose to establish cross-correlationbetweeninvitroassays,humaninducedpluripotentstemcell(iPSC)modelsandpostmortem braintissue.WewillfocusoniPSCsderivedfrompatientswithfamilialandsporadicsynucleinopathiesthatare matchedtopostmortembrain,includingcaseswithconcomitantlevelsofAD(?-amyloidandtau)pathology.Our approachesnotonlypromisetoshedlightontheformationandconsequencesofamyloidstrainsinADRD,but willalsopointatpotentialinterventionscenteredaroundthetransientinteractionof?Swithlipidmembranes.